This project is designed to evaluate multiple factors related, either singly or in combination, to the pathogenesis of neurological diseases. Focus is currently placed on multiple sclerosis. Magnetic resonance imaging is important in the assessment of MS and the recent detection of gadolinium-enhancing lesions by this technology provides evidence that an early event in the pathogenesis is breakdown of the blood-brain barrier. To determine the frequency and natural history of such lesions, a group of patients with mild, early MS are being studied monthly. MRI studies are being conducted in familial leukodystrophy. Particular attention is being given to genetic and immunological factors which contribute to pathogenesis of MS. Genes encoding for HLA molecules and the T-cell receptors are being evaluated in patients with sporadic disease and families with multiple affected members. Trials of experimental therapeutic agents for MS are conducted. The findings from MRI investigations with gadolinium enhancement are being used to develop strategies for the future evaluation of new treatments. A recent double-blind study of cyclosporine A showed that patients treated with this agent progress less rapidly than patients who received placebo; however, renal toxicity was a significant side effect. The relationship between cyclosporine A treatment and nephrotoxicity is currently being assessed in an open-label study. The chronic myelopathy, HTLV-I-associated myelopathy/tropical spastic paraplegia (HAM/TSP) is being investigated. Immunological, clinical, and MRI findings in HAM/TSP are being compared to normal carrier of HTLV-I.